Tumour Markers

Definition

Tumour markers are substances present in abnormally high concentrations in body fluids or tissue from patients with cancer. They are surrogate indicators that can help confirm a cancer diagnosis, monitor treatment effectiveness, estimate prognosis, and/or predict whether a specific therapy is likely to be effective. They may be tumour-derived or tumour-associated, and include a wide variety of molecular species: proteins, hormones, enzymes, glycoproteins, mucins, and molecular/genomic markers.

Tietz Textbook of Laboratory Medicine, 7th Ed, p. 1011

Types of Serum Tumour Markers

Three functional categories of tumour markers are commonly recognised (Henry's Clinical Diagnosis and Management):

1. Oncofetal Antigens

Normally expressed during fetal development but re-expressed in malignant cells:

AFP (alpha-fetoprotein) - hepatocellular carcinoma, germ cell tumours
CEA (carcinoembryonic antigen) - colorectal cancer (most widely used GI marker)
beta-hCG (human chorionic gonadotropin) - germ cell/testicular tumours, gestational trophoblastic neoplasia

2. Mucin/Glycoprotein CA Antigens (Monoclonal Antibody-Defined)

Marker	Major Malignancy
CA 125	Ovarian carcinoma
CA 19-9	Pancreatic carcinoma
CA 15-3	Breast carcinoma
CA 72-4	Gastric carcinoma
HER2/neu	Breast carcinoma

3. Polypeptide Hormones and Enzymes

PSA (prostate-specific antigen) - prostate cancer; organ-specific but not cancer-specific (elevated in BPH and prostatitis too)
Calcitonin - medullary carcinoma of the thyroid; ectopically in bronchogenic carcinoma
LDH (lactate dehydrogenase) - testicular cancer staging/prognosis
Chromogranin A - pheochromocytoma, medullary thyroid carcinoma, small cell lung carcinoma, pancreatic neuroendocrine tumours
Thyroglobulin - papillary and follicular thyroid cancer (post-thyroidectomy monitoring)
CYFRA 21-1 - cytokeratin 19 fragment; useful in squamous cell lung carcinoma

Clinical Applications

1. Screening

Only PSA has widespread application in screening (prostate cancer). Most markers have insufficient sensitivity/specificity for population screening. The UK does not routinely screen with PSA, but men can request testing.

2. Diagnosis

Tumour marker results rarely replace biopsy for primary diagnosis. A raised result never definitively indicates malignancy; a normal result never excludes it. Use is recommended only when clinical presentation raises specific cancer suspicion.

3. Prognosis and Risk Stratification

PSA stratifies men with newly diagnosed prostate cancer into risk groups
AFP, beta-hCG, LDH contribute to the International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic classification for testicular cancer
ER, PR, HER2/neu are mandatory prognostic and predictive markers in breast cancer on surgical specimens

4. Treatment Prediction

ER (oestrogen receptor): Positive = likely benefit from antiestrogen therapy (tamoxifen, aromatase inhibitors). Negative = unlikely to benefit
HER2/neu overexpression: Predicts response to trastuzumab (Herceptin); associated with poor prognosis

5. Monitoring Therapy and Detecting Recurrence

This is the most validated use of tumour markers, particularly for:

Choriocarcinoma (beta-hCG, AFP) - mandatory
Germ cell tumours (AFP, beta-hCG, LDH)
Colorectal cancer (CEA) - post-surgical surveillance
Ovarian cancer (CA 125)
Prostate cancer (PSA after treatment)

Clinical Presentations and Markers

Marker	Primary Cancer	Typical Presentation	Also Raised In
AFP	Germ cell tumour; HCC	Testicular swelling; ascites/jaundice	Gastric, colorectal, biliary, pancreatic, lung
CA 125	Ovarian cancer	Pelvic mass; bloating	Breast, endometrial, lung, pancreas
CA 19-9	Pancreatic cancer	Obstructive jaundice, weight loss	Colorectal, gastric, HCC, ovary
CEA	Colorectal cancer	Abdominal pain, bleeding, palpable mass	Breast, gastric, lung, mesothelioma
hCG	Germ cell tumour; GTN	Testicular swelling; cannonball secondaries on CXR	Lung cancer
Paraproteins	Multiple myeloma	Bone pain, anaemia, recurrent infections	-
PSA	Prostate cancer	LUTS, acute retention, bone pain	None (organ specific)

Tietz Textbook of Laboratory Medicine, 7th Ed, Table 33.13

Testicular Cancer Markers (Summary)

AFP, beta-hCG, and LDH are the three routinely used markers for testicular cancer. They provide insight into:

Likely histological subtype (e.g., AFP not elevated in pure seminoma)
Success of treatment
Recurrence
IGCCCG prognostic categorisation

Bailey and Love's Short Practice of Surgery, 28th Ed

Important Practical Principles

Pretreatment baseline is essential - always obtain before starting therapy
Confirm on repeat specimen before making therapy decisions
Half-life matters - e.g., PSA half-life is ~3-4 days; wait at least 30 days post-surgery before assessing success of prostate cancer resection
Organ/metabolic disease can falsely elevate markers - CEA rises in liver disease (impaired clearance); beta-2 microglobulin rises in renal failure
Multiple markers improve sensitivity - tumour heterogeneity means no single marker is 100% sensitive; combining markers can improve detection rates
Ectopic expression - some markers appear in unexpected cancers at advanced/metastatic stages, often indicating poor prognosis (e.g., AFP in metastatic GI cancer with normal LFTs)

PSA - Key Points

Glycoprotein produced by prostatic epithelial cells
Not significantly altered by digital rectal examination (DRE)
Significantly altered by UTI - returns to baseline 6 weeks after infection treatment
Artificially lowered (up to 2-fold) by 5-alpha reductase inhibitors (finasteride, dutasteride)
Also lowered by aspirin, statins, and thiazide diuretics
No single "normal" threshold - influenced by age, ethnicity, and family history

Bailey and Love's Short Practice of Surgery, 28th Ed, p. 1473

Sources: Tietz Textbook of Laboratory Medicine (7th Ed); Henry's Clinical Diagnosis and Management by Laboratory Methods; Bailey and Love's Short Practice of Surgery (28th Ed); Schwartz's Principles of Surgery (11th Ed).

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